Processes for the preparation of 3-(pyrrol-2-yl)methylene)-2-pyrrolones using 2-silyloxy-pyrroles

Abstract

The present invention provides for synthetic processes for the making of substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolones, including sunitinib. The present invention also provides for a process of crystallizing substantially pure sunitinib L-malate.

The invention claimed is: 
     
       1. A process for preparing a substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolone of formula (I) or a salt thereof: 
       
         
           
           
               
               
           
         
         comprising:
 a) reacting a compound of formula (II): 
 
       
       
         
           
           
               
               
           
         
         
            or a compound of formula (V): 
         
       
       
         
           
           
               
               
           
         
         
           with a compound of formula (III): 
         
       
       
         
           
           
               
               
           
         
         
            to obtain the substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolone of formula (I), wherein R 1  and R 4  are optionally and independently H, C 1 -C 8  alkyl, aryl, benzyl, heteroaryl, silyl; R 2  and R 3  are optionally and independently H, C 1 -C 8  alkyl, aryl, heteroaryl, or together form a substituted or unsubstituted ring; R independently is C 1 -C 8  alkyl, aryl, H or an oxygen-based substituent; R 5  is H, C 1 -C 8  alkyl, aryl, heteroaryl, or COR′ wherein R′ is H, C 1 -C 8  alkyl, aryl, heteroaryl, O—C 1 -C 8  alkyl, N,N-di-C 1 -C 8  alkyl, NH—C 1 -C 8  alkyl or N, N-diaryl; R 6 , R 7 , and R 8  independently are H, C 1 -C 8  alkyl, aryl, heteroaryl, silyl, COR″ wherein R″ is H, C 1 -C 8  alkyl, aryl, benzyl, heteroaryl, substituted or unsubstituted heterocyclic, OH, SH, NH 2 , O—C 1 -C 8  alkyl, NH—C 1 -C 12  alkyl, N,N-di-C 1 -C 12  alkyl, N,N-diaryl, N,N-dibenzyl, or S—C 1 -C 8  alkyl; and optionally where R 5  and R 6  together form a ring; and optionally where R 6  and R 7  together form a ring; and optionally where R 7  and R 8  together form a substituted or unsubstituted ring, and R 9  and R 10  are independently selected from C 1 -C 12  alkyl or silyl, or in the alternative, R 9  and R 10  form a ring together; X is Cl, Br, I, triflate (OTf), OP(O)Cl 2  OP(O)Br 2  OH, tosylate (TsO), mesylate (MsO), or R′″CO 2 , where R′″ is C 1 -C 8  alkyl, aryl or heteroaryl; and 
           b) optionally reacting the substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolone of formula (I) with a salt forming agent to obtain the salt thereof; 
           wherein the reaction between the compound of formula (II) and the compound of formula (III) in the reacting step a) is conducted in the presence of a catalyst and in a solvent. 
         
       
     
     
       2. The process according to  claim 1  wherein the substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolone of formula (I) is selected from the following compounds: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       3. The process of  claim 1 , wherein the catalyst is a Lewis acid or Brønsted acid catalyst. 
     
     
       4. The process of  claim 3  where the Lewis acid is selected from the group consisting of trimethylsilyl trifluoromethanesulfonate (TMSOTf), tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), trimethylsilyl methanesulfonate (TMSOMs), BF 3 .Et 2 O, SnCl 4 , LiClO 4 , M(OTf) 3  (where OTf is triflate and M is a lanthanide ion, or Bi), M(OTf) 4  (where OTf is triflate and M is a transition metal ion), ZnCl 2 , ZnBr 2 , ZnI 2 , AlCl 3 , MgCl 2 , MgBr 2  and TiCl 4 . 
     
     
       5. The process of  claim 4 , wherein the Lewis acid catalyst is trimethylsilyl trifluoromethanesulfonate (TMSOTf). 
     
     
       6. The process of  claim 3 , wherein the Brønsted acid is selected from the group consisting of carboxylic acids and halocarboxylic acids. 
     
     
       7. The process of  claim 5 , wherein the molar percentage of trimethylsilyl trifluoromethanesulfonate (TMSOTf) is 5 mol % to 200 mol % with respect to the compound of formula (II). 
     
     
       8. The process of  claim 1  further comprising silylating a compound of formula (IV) with a silylating agent: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2  and R 3  are defined in  claim 1  to obtain the compound of formula (III). 
       
     
     
       9. The process of  claim 8 , wherein the silylating agent is selected from the group consisting of hexamethyldisilazane (HMDS), N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), trimethylsilyl chloride (TMSCl), N,O -bis(trimethylsilyl)acetamide (BSA), tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and tert-butyldimethylsilyl chloride (TBSCl). 
     
     
       10. The process of  claim 8 , wherein the silylating is conducted in the presence of a solvent, or in the absence of a solvent and the silylating agent acts as a solvent. 
     
     
       11. The process of  claim 1 , wherein the salt forming agent is selected from the group consisting of D- or L-malic acid, camphorsulfonic acid, tartaric acid, trifluoroacetic acid, benzoic acid (BzOH), acetic acid (AcOH), methanesulfonic acid (MsOH), HCl, HBr, H 2 SO 4 , HF, and 3HF.Et 3 N. 
     
     
       12. The process of  claim 1 , wherein the compound of formula (I) is sunitinib with the following formula: 
       
         
           
           
               
               
           
         
       
     
     
       13. The process of  claim 1  wherein the compound of formula (I) is sunitinib and the process further comprises steps of:
 i) quenching crude sunitinib obtained from the reacting step (a) with an aqueous base to give a wet cake; 
 ii) reslurrying the wet cake with an alcohol and filtering; and 
 iii) drying the filter cake to give substantially pure sunitinib. 
 
     
     
       14. The process of  claim 1  wherein the salt of the substituted 3-((pyrrol-2-yl)methylene)-2-pyrrolone of the formula (I) is sunitinib L-malate, and the step b) is conducted to obtain a crude sunitinib L-malate in solid form, the process further comprises steps of:
 i) pre-heating dimethylsulfoxide (DMSO) to about 45° C.; 
 ii) adding the crude sunitinib L-malate in solid form to the pre-heated dimethylsulfoxide (DMSO); 
 iii) adding methyl isobutyl ketone (MIBK) into the mixture of ii); and 
 iv) cooling and filtering the mixture of 11i) to provide substantially pure sunitinib L-malate. 
 
     
     
       15. The process of  claim 1 , wherein the solvent is selected from the groups consisting of nitriles, haloalkanes, aromatics, esters, ethers, amides, sulfoxides, ketones, alkanes, and mixtures thereof. 
     
     
       16. The process of  claim 1 , wherein the solvent is selected from the group consisting of 1,2-dichloroethane (DCE), dichloromethane (DCM), chloroform (CHCl 3 ), toluene (PhMe), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMAC), N-methyl-2-pyrrolidone (NMP), dimethylsulfoxide (DMSO), ethyl acetate (EtOAc), acetonitrile (MeCN), n-heptane, 1,4-dioxane, acetone, methyl isobutyl ketone (MIBK), and tetrahydrofuran (THF), and mixtures thereof. 
     
     
       17. The process of  claim 1 , wherein the reacting step a) is conducted at a temperature between 0° C. and 200° C. 
     
     
       18. The process of  claim 1  further comprising reacting a compound of formula (VI): 
       
         
           
           
               
               
           
         
         wherein R 6  and R 7  and R 8  are defined as in  claim 1 , with a salt of formula (VII): 
       
       
         
           
           
               
               
           
         
         wherein X is as defined in  claim 1 , and X′ is Cl, Br, or triflate (OTf); R 5  is H or C 1 -C 8  alkyl, R 9  and R 10  are independently C 1 -C 12  alkyl, or in the alternative, R 9  and R 10  form a ring together, to prepare the compound of formula (V). 
       
     
     
       19. The process of  claim 1  further comprising reacting the compound of formula (II): 
       
         
           
           
               
               
           
         
         wherein R 5 , R 6 , R 7  and R 8  are defined as in  claim 1 , with a compound of formula (VIII) or an acid (HX) salt thereof: 
       
       
         
           
           
               
               
           
         
         wherein R 9  and R 10  are independently C 1 -C 12  alkyl, or in the alternative, R 9  and R 10  form a ring together, and X is defined as in  claim 1 , to obtain the compound of formula (V). 
       
     
     
       20. The process of  claim 1  wherein the reaction between the compound of formula (III) and the compound of formula (V) in the reacting step a) is conducted in the absence of a Lewis acid or Brønsted acid catalyst. 
     
     
       21. The process of  claim 1  wherein the reaction between the compound of formula (III) and the compound of formula (V) in the reacting step a) is conducted in a solvent.